Immunoglobulin (Ig) A is acknowledged to be important for the maintenance of human health, although its physiological role, especially that of circulating plasma IgA, is poorly understood. The presence and local production of IgA having specific antibody activity against periodontal pathogens have been demonstrated in the circulation and in inflamed gingival tissue. The overall objective of this project is therefore to elucidate the functions of human IgA antibodies with respect to periodontal disease. It is hypothesized that IgA antibodies are essentially anti-inflammatory in nature, and it is postulated that they have a role in the regulation of the normal inflammatory-immune response cycle, which is perturbed by periodontal pathogens leading to exacerbation and perpetuation of inflammation. To examine this hypothesis the following in vitro studies are proposed using human Ig and immunocompetent cells. (i) To determine the effect of IgA antibodies of monomeric and polymeric form (in comparison with IgG antibodies) on the functional activation of antigen-presenting cells (peripheral blood monocytes and dendritic cells) by antigens, and their ability to stimulate T cells to proliferate and secrete cytokines and B cells to differentiate into Ig-secreting cells. Because IgA antibodies interfere with complement fixation, the importance of fixed C3b or C3d,g in the antigen-antibody complexes as a ligand for complement receptors on antigen-presenting cells will be assessed. The effect of cleaving IgA1 antibodies with IgA1 protease, which is produced by several subgingival plague bacteria, will also be investigated. (ii) To determine the effect of IgA antibodies on the stimulation of sensitized B cells by T-dependent and T-independent antigens, in terms of their ability to present T-dependent antigens to T cells, and to respond to both types of antigens with or without T cells by differentiating into Ig-secreting cells. The importance of fixed C3b or C3d,g in ligating B cell receptors for complement fragment C3d,g (CR2) in these responses will be determined. Because Fc-alpha fragments (obtained by cleavage of IgA1 with IgA1 protease) can activate and fix C3b, their ability to stimulate B cells by co-ligating the CR2 will also be investigated. If the hypothesis that IgA antibodies regulate ongoing immune responses is sustained, then measures to enhance the IgA antibody response to periodontal pathogens, and to overcome the mechanisms by which these organisms interfere with the postulated regulatory activities of IgA antibodies, should contribute to the alleviation of periodontal disease. It is expected that novel information on the physiological functions of human IgA antibodies and their role in periodontal disease will result from the proposed studies.